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Open AccessArticle

A Multilevel Study of Eupatorin and Scutellarein as Anti-Amyloid Agents in Alzheimer’s Disease

by

Aikaterini E. I. Rizou

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Georgia I. Nasi

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Yiorgos Paikopoulos

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Dimitra S. Bezantakou

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Konstantina D. Vraila

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Panagiotis M. Spatharas

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Vassiliki A. Iconomidou

Biomedicines 2023, 11(5), 1357; https://doi.org/10.3390/biomedicines11051357 - 04 May 2023

Viewed by 551

Abstract

Today, Alzheimer’s disease (AD)—the most common neurodegenerative disorder, which affects 50 million people—remains incurable. Several studies suggest that one of the main pathological hallmarks of AD is the accumulation of abnormal amyloid beta (Aβ) aggregates; therefore, many therapeutic approaches focus on anti-Aβ aggregation [...] Read more.

Today, Alzheimer’s disease (AD)—the most common neurodegenerative disorder, which affects 50 million people—remains incurable. Several studies suggest that one of the main pathological hallmarks of AD is the accumulation of abnormal amyloid beta (Aβ) aggregates; therefore, many therapeutic approaches focus on anti-Aβ aggregation inhibitors. Taking into consideration that plant-derived secondary metabolites seem to have neuroprotective effects, we attempted to assess the effects of two flavones—eupatorin and scutellarein—on the amyloidogenesis of Aβ peptides. Biophysical experimental methods were employed to inspect the aggregation process of Aβ after its incubation with each natural product, while we monitored their interactions with the oligomerized Aβ through molecular dynamics simulations. More importantly, we validated our in vitro and in silico results in a multicellular organismal model—namely, Caenorhabditis elegans—and we concluded that eupatorin is indeed able to delay the amyloidogenesis of Aβ peptides in a concentration-dependent manner. Finally, we propose that further investigation could lead to the exploitation of eupatorin or its analogues as potential drug candidates. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in Drug Discovery)

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Open AccessArticle

Abscopal Effect on Bone Metastases from Solid Tumors: A Systematic Review and Retrospective Analysis of Challenge within a Challenge

by

Miriam Tomaciello

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Miriam Conte

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Francesca Romana Montinaro

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Arianna Sabatini

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Giorgia Cunicella

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Federico Di Giammarco

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Paolo Tini

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Giovanni Luca Gravina

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Enrico Cortesi

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Giuseppe Minniti

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Giuseppe De Vincentis

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Viviana Frantellizzi

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Francesco Marampon

Biomedicines 2023, 11(4), 1157; https://doi.org/10.3390/biomedicines11041157 - 12 Apr 2023

Viewed by 1005

Abstract

Background: Abscopal effect (AE) describes the ability of radiotherapy (RT) to induce immune-mediated responses in nonirradiated distant metastasis. Bone represents the third most frequent site of metastasis and an immunologically favorable environment for the proliferation of cancer cells. We revised the literature, searching [...] Read more.

Background: Abscopal effect (AE) describes the ability of radiotherapy (RT) to induce immune-mediated responses in nonirradiated distant metastasis. Bone represents the third most frequent site of metastasis and an immunologically favorable environment for the proliferation of cancer cells. We revised the literature, searching documented cases of AE involving bone metastases (BMs) and evaluated the incidence of AE involving BMs in patients requiring palliative RT on BMs or non-BMs treated at our department. Methods: Articles published in the PubMed/MEDLINE database were selected using the following search criteria: ((abscopal effect)) AND ((metastases)). Patients with BMs, who underwent performed bone scintigraphy before and at least 2–3 months after RT, were selected and screened between January 2015 and July 2022. AE was defined as an objective response according to the scan bone index for at least one nonirradiated metastasis at a distance > 10 cm from the irradiated lesion. The primary endpoint was the rate of AE on BMs. Results: Ten cases experiencing AE of BMs were identified from the literature and eight among our patients. Conclusions: The analysis performed here suggests the use of hypofractionated radiotherapy as the only triggering factor for AE of BMs through the activation of the immune response. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in Drug Discovery)

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Open AccessArticle

The Potassium Channel Blocker β-Bungarotoxin from the Krait Bungarus multicinctus Venom Manifests Antiprotozoal Activity

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Trang Thuy Thi Nguyen

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Biomedicines 2023, 11(4), 1115; https://doi.org/10.3390/biomedicines11041115 - 07 Apr 2023

Viewed by 673

Abstract

Protozoal infections are a world-wide problem. The toxicity and somewhat low effectiveness of the existing drugs require the search for new ways of protozoa suppression. Snake venom contains structurally diverse components manifesting antiprotozoal activity; for example, those in cobra venom are cytotoxins. In [...] Read more.

Protozoal infections are a world-wide problem. The toxicity and somewhat low effectiveness of the existing drugs require the search for new ways of protozoa suppression. Snake venom contains structurally diverse components manifesting antiprotozoal activity; for example, those in cobra venom are cytotoxins. In this work, we aimed to characterize a novel antiprotozoal component(s) in the Bungarus multicinctus krait venom using the ciliate Tetrahymena pyriformis as a model organism. To determine the toxicity of the substances under study, surviving ciliates were registered automatically by an original BioLaT-3.2 instrument. The krait venom was separated by three-step liquid chromatography and the toxicity of the obtained fractions against T. pyriformis was analyzed. As a result, 21 kDa protein toxic to Tetrahymena was isolated and its amino acid sequence was determined by MALDI TOF MS and high-resolution mass spectrometry. It was found that antiprotozoal activity was manifested by β-bungarotoxin (β-Bgt) differing from the known toxins by two amino acid residues. Inactivation of β-Bgt phospholipolytic activity with p-bromophenacyl bromide did not change its antiprotozoal activity. Thus, this is the first demonstration of the antiprotozoal activity of β-Bgt, which is shown to be independent of its phospholipolytic activity. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in Drug Discovery)

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Open AccessArticle

Carnosic Acid Ameliorates Indomethacin-Induced Gastric Ulceration in Rats by Alleviating Oxidative Stress and Inflammation

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Ali Taghizadehghalehjoughi

Biomedicines 2023, 11(3), 829; https://doi.org/10.3390/biomedicines11030829 - 09 Mar 2023

Viewed by 821

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and indomethacin (IND) are the most commonly prescribed for inflammation or pain. However, widespread use causes several adverse effects, such as gastric ulcers, upper gastric system bleeding, and erosions. Carnosic acid (CA) is an important natural [...] Read more.

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and indomethacin (IND) are the most commonly prescribed for inflammation or pain. However, widespread use causes several adverse effects, such as gastric ulcers, upper gastric system bleeding, and erosions. Carnosic acid (CA) is an important natural antioxidant found in rosemary (Rosmarinus essentials) and exhibits a protective effect by suppressing oxidative stress and inflammation. This study aimed to investigate the impact of CA on IND-induced gastric ulceration. Wistar male rats received CA (100 mg/kg) or esomeprazole (ESP) (20 mg/kg, standard drug) by oral gavage for 14 days, after that gastric ulceration was induced by oral administration of 100 mg/kg IND. CA pretreatment attenuated both gross morphological lesions and histopathological alterations. CA strongly reduced IND-induced oxidative stress, verified by a decrease in MDA (p < 0.001) and TOS levels (p < 0.05). Furthermore, an IND-dependent increase in CAT (p < 0.001) and GPx (p < 0.01) activities, as well as a reduction in GSH levels (p < 0.01), were ameliorated by CA pretreatment. CA also attenuated inflammatory damage by suppressing IL-1β (p < 0.01), IL-6 (p < 0.01), and TNFα (p < 0.001) production and increasing Nrf2/HO-1 (p < 0.05) expressions. In conclusion, CA shows a gastroprotective effect by reducing oxidative stress and attenuating inflammation. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in Drug Discovery)

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Open AccessArticle

Ligand-Receptor Interactions of Lamivudine: A View from Charge Density Study and QM/MM Calculations

by

Alexander A. Korlyukov

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Adam. I. Stash

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Alexander R. Romanenko

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Damian Trzybiński

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Krzysztof Woźniak

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Anna V. Vologzhanina

Biomedicines 2023, 11(3), 743; https://doi.org/10.3390/biomedicines11030743 - 01 Mar 2023

Viewed by 630

Abstract

The nature and strength of interactions for an anti-HIV drug, Lamivudine, were studied in a pure crystal form of the drug and the ligand–receptor complexes. High-resolution single-crystal X-ray diffraction studies of the tetragonal polymorph allowed the drug’s experimental charge density distribution in [...] Read more.

The nature and strength of interactions for an anti-HIV drug, Lamivudine, were studied in a pure crystal form of the drug and the ligand–receptor complexes. High-resolution single-crystal X-ray diffraction studies of the tetragonal polymorph allowed the drug’s experimental charge density distribution in the solid state to be obtained. The QM/MM calculations were performed for a simplified model of the Lamivudine complex with deoxycytidine kinase (two complexes with different binding modes) to reconstruct the theoretical charge density distribution. The peculiarities of intramolecular interactions were compared with previously reported data for an isolated molecule. Intermolecular interactions were revealed within the quantum theory of ‘Atoms in Molecules’, and their contributions to the total crystal energy or ligand–receptor binding energy were evaluated. It was demonstrated that the crystal field effect weakened the intramolecular interactions. Overall, the energies of intermolecular interactions in ligand–receptor complexes (320.1–394.8 kJ/mol) were higher than the energies of interactions in the crystal (276.9 kJ/mol) due to the larger number of hydrophilic interactions. In contrast, the sum of the energies of hydrophobic interactions was found to be unchanged. It was demonstrated by means of the Voronoi tessellation that molecular volume remained constant for different molecular conformations (250(13) Å³) and increased up to 399 Å³ and 521(30) Å³ for the Lamivudine phosphate and triphosphate. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in Drug Discovery)

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Open AccessArticle

Antiparasitic Activity of Fluorophenyl-Substituted Pyrimido[1,2-a]benzimidazoles

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Biomedicines 2023, 11(1), 219; https://doi.org/10.3390/biomedicines11010219 - 14 Jan 2023

Viewed by 1153

Abstract

A series of fourteen pyrimido[1,2-a]benzimidazole compounds was prepared by straightforward heterocyclic chemistry and oxidation methods. The new pyrimidobenzimidazole derivative 2a with a 3-fluorophenyl substituent was identified as a new antiparasitic compound showing excellent activities against Leishmania major parasites. 2a was highly [...] Read more.

A series of fourteen pyrimido[1,2-a]benzimidazole compounds was prepared by straightforward heterocyclic chemistry and oxidation methods. The new pyrimidobenzimidazole derivative 2a with a 3-fluorophenyl substituent was identified as a new antiparasitic compound showing excellent activities against Leishmania major parasites. 2a was highly active against L. major promastigotes and amastigotes with EC₅₀ values in the nanomolar concentration range. Compound 3b was less active than 2a against L. major, but more active against Toxoplasma gondii with considerable selectivity. Hence, two promising and selective antiparasitic drug candidates 2a and 3b for the treatment of two parasitic diseases were identified, which can be prepared by green chemistry methods using simple one-pot reactions and oxidation procedures, respectively. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in Drug Discovery)

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Review

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Open AccessReview

G-Quadruplexes in c-MYC Promoter as Targets for Cancer Therapy

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Biomedicines 2023, 11(3), 969; https://doi.org/10.3390/biomedicines11030969 - 21 Mar 2023

Cited by 1 | Viewed by 812

Abstract

Cancer is a societal burden demanding innovative approaches. A major problem with the conventional chemotherapeutic agents is their strong toxicity and other side effects due to their poor selectivity. Uncontrolled proliferation of cancer cells is due to mutations, deletions, or amplifications in genes [...] Read more.

Cancer is a societal burden demanding innovative approaches. A major problem with the conventional chemotherapeutic agents is their strong toxicity and other side effects due to their poor selectivity. Uncontrolled proliferation of cancer cells is due to mutations, deletions, or amplifications in genes (oncogenes) encoding for proteins that regulate cell growth and division, such as transcription factors, for example, c-MYC. The direct targeting of the c-MYC protein has been attempted but so far unsuccessfully, as it lacks a definite binding site for the modulators. Meanwhile, another approach has been explored since the discovery that G-quadruplex secondary DNA structures formed in the guanine-rich sequences of the c-MYC promoter region can downregulate the transcription of this oncogene. Here, we will overview the major achievements made in the last decades towards the discovery of a new class of anticancer drugs targeting G-quadruplexes in the c-MYC promoter of cancer cells. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in Drug Discovery)

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Open AccessReview

DNA Gyrase as a Target for Quinolones

by

Angela C. Spencer

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Siva S. Panda

Biomedicines 2023, 11(2), 371; https://doi.org/10.3390/biomedicines11020371 - 27 Jan 2023

Cited by 1 | Viewed by 1516

Abstract

Bacterial DNA gyrase is a type II topoisomerase that can introduce negative supercoils to DNA substrates and is a clinically-relevant target for the development of new antibacterials. DNA gyrase is one of the primary targets of quinolones, broad-spectrum antibacterial agents and are used [...] Read more.

Bacterial DNA gyrase is a type II topoisomerase that can introduce negative supercoils to DNA substrates and is a clinically-relevant target for the development of new antibacterials. DNA gyrase is one of the primary targets of quinolones, broad-spectrum antibacterial agents and are used as a first-line drug for various types of infections. However, currently used quinolones are becoming less effective due to drug resistance. Common resistance comes in the form of mutation in enzyme targets, with this type being the most clinically relevant. Additional mechanisms, conducive to quinolone resistance, are arbitrated by chromosomal mutations and/or plasmid-gene uptake that can alter quinolone cellular concentration and interaction with the target, or affect drug metabolism. Significant synthetic strategies have been employed to modify the quinolone scaffold and/or develop novel quinolones to overcome the resistance problem. This review discusses the development of quinolone antibiotics targeting DNA gyrase to overcome bacterial resistance and reduce toxicity. Moreover, structural activity relationship (SAR) data included in this review could be useful for the development of future generations of quinolone antibiotics. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in Drug Discovery)

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